High measles mortality in infancy related to intensity of exposure

In a West African urban community, measles infection in infants was examined over 5 years (1979-1983). In the age group 0 to 11 months, measles mortality was higher among secondary cases (infected in the house) than among index cases (infected outside the house), and the proportion of secondary cases was significantly higher for this age group than for older children. Intensive exposure related to the social pattern of disease transmission may be important in explaining the high infant mortality observed with measles in developing countries. Mortality during the first 12 months of life increased with age, presumably because of the decrease of maternally derived measles antibodies. In children younger than 6 months of age, who are usually considered to be protected by maternal antibody, intensive exposure may lead to infection, as demonstrated by a high level of measles-specific antibodies in some children exposed to an older sibling with measles. The aim of public health policies should be to change conditions of exposure.     

Passive immunity to measles in the breastmilk and cord blood of some nigerian subjects

Maternal and cord blood collected from 33 Nigerian mother-child pairs were tested for measles-sepcific IgG. All 33 had protective measles antibodies at the time of delivery with a positive correlation of r = 0.87. Determination of the rate of waning of these antibodies revealed that 58 per cent of these children had lost the protective maternal antibody by the age of 4 months and only 3 per cent of the children had enough antibody to protect them between the ages of 6-9 months. Fifty-five colostrum samples from the same mothers and 347 breastmilk samples collected at various periods of breastfeeding also showed that anti-measles IgA had dropped below the protective cut-off within the first 2 weeks of birth. It is evident that the Nigerian child is born with solid anti-measles antibody but the rate of waning has left a large number unprotected before the first dose of the vaccine. There is an urgent need to review the measles vaccination programme in Nigeria to protect these susceptible infants.     

Transplacental immunity and waning of maternal antibody in measles

Since transplacental immunity and waning of maternally derived measles specific antibodies play an important role in determining the optimum age for vaccination of infants against measles, a study was carried out in which 150 paired samples and 581 infant serum samples were tested for measles specific antibodies. Out of these paired samples, 132 pairs showed measles antibodies in both mother and cord. HAI antibody was absent in 3 paired samples whereas, 5 mothers could not pass on the antibodies in the cord samples. In the remaining 10 serum samples only cord blood showed the presence of antibodies without the detectable level of antibodies in mother. Statistically no significant difference between the mother and cord blood titers was observed by applying the student ‘t’ test for comparison of the mean (t=0.01). Analysis of 581 infant serum samples for prevalence of maternal antibodies indicated that 83% of the samples at the age of 3 months or below had measles antibodies but with the increase in age there was tremendous loss with only 19–20% at the age of 6–7 months. After 7 months the percentage of infants which had antibody varied from 11–13%. There was negative correlation between age and seropositivity (r=−0.72) which was highly significant (p<0.05).     

Elimination of maternal antibodies against measles (is the policy of vaccinating children younger than nine months of age suitable for Turkey?).

Maternal antibodies against measles in 223 healthy children aged 22 to 31 weeks were studied. The ratio of children with detectable antibodies declined from 61.4 percent at 22-23 weeks of age to 20 percent at 26-27 weeks of age. Since the minimum proportion of antibody-positive children (15.6% at 26-27 weeks of age) is still higher than the optimum proportion (5%), the Schwarz vaccine which is used mostly in measles immunization seems not to be effective to obtain a high seroconversion rate in our infants. We suggest that the Edmonston-Zagreb strain of measles vaccine be used for infants under 9 months of age in Turkey.     

Immune status following measles vaccination in infants and evaluation for the need of revaccination

In this prospective study, immune status of children vaccinated in infancy was determined at age 12-18 months. In 200 children, preimmunization protective measles hemagglutination (HI) antibody titres (greater than or equal to 1:8) were present in 38.5% of children of 6-8 months, the frequency decreased to 17.6 and 14.3% in age groups 9-11 and 12-18 months, respectively followed by an increasing incidence of 52.5% in those more than 18 months of age. Paired measles HI titre was estimated in 56 children, the post vaccination sample was taken at age 12-18 months, 3-9 months after measles vaccination. Most of the children (98.0%), with no detectable antibody titre, had a protective titre. Again a significant number (p less than 0.001) of children aged 12-18 months had protective HI titres compared to non-vaccinated. These findings suggest that when vaccinated at 9-11 months in our country, there is no need for revaccination later.     

The duration of maternal measles antibodies in children

The most important factor affecting the success of measles immunization is the disappearance of maternal anti-measles antibodies. In order to determine the optimum age for measles vaccination and to contribute towards the Expanded Programme on Immunization as currently applied in Turkey, we investigated the rate of disappearance of anti-measles antibodies. The study population consisted of 124 healthy infants aged 1-15 months from Erzurum, Erzincan, and Kars. The overall proportion of seropositivity, which is the result of the presence of maternal anti-measles antibodies, was 67/124 (54 per cent). The proportion of infants with detectable antibodies declined progressively with increasing age. The distribution of maternal antibody levels with respect to age showed a progressive reduction with increasing age from 7 months to 15 months. Thus the proportion of antibody-positive infants declined from 50 per cent at 7-9 months to 10 per cent at 13-15 months. While an evident decrease occurred during these months, no important decline was observed up to 9 months of age. The results of this study show that the minimum proportion of antibody-positive infants (10 per cent at 13-15 months of age) is still higher than the optimum proportion (5 per cent). The Schwarz vaccine, which is used mostly in measles immunization, seems not to be effective to obtain a high seroconversion rate in our infants. Edmonston-Zagreb vaccine strain should be given to children under the age of 15 months in eastern Turkey. In addition, serological studies should be performed periodically, and vaccination programmes appropriate for our country should be determined according to these data.     

No strong long-term effect of vitamin A supplementation in infancy on CD4 and CD8 T-cell subsets. A community study from Guinea-Bissau, West Africa

The World Health Organization recommends that 100,000 IU of vitamin A be given to infants between 6 and 12 months of age at the same time as measles vaccination in order to prevent vitamin A deficiency. In the present study, our aim was to assess the effect of vitamin A supplementation on T-cell subsets in a randomized factorial design, seeking a possible modifying effect of measles vaccination. Three hundred children were allocated either to two doses of measles vaccine at 6 and 9 months of age or to poliomyelitis vaccine at age 6 months and measles vaccine at age 9 months. Within each group, infants were to receive two doses of vitamin A or two doses of placebo at 6 and 9 months of age. We found no significant effect of vitamin A supplementation on CD4 and CD8 T-cell subsets at 3 and 9 months after supplementation. We found no effect of measles vaccine and no interaction between vitamin A supplementation and measles vaccine. Based on these observations, vitamin A supplementation does not seem to have a strong long-term effect on CD4 and CD8 T-cell subsets in infants without clinical vitamin A deficiency.     

Successful immunization of infants at 6 months of age with high dose Edmonston-Zagreb measles vaccine. Cite Soleil/JHU Project Team

A group of 2097 Haitian infants 6 to 11 months of age were randomized to receive Schwarz or Edmonston-Zagreb strain measles vaccines containing 10- to 500-fold more vaccine viral particles than standard potency vaccines. No unusual adverse reactions were noted. Edmonston-Zagreb vaccines were more effective than equivalent doses of Schwarz vaccines as measured by the proportion of vaccinated children with measles antibody concentrations greater than or equal to 200 mIU/ml 2 months after vaccination and the persistence of antibody at 18 to 24 months of age. High titer Edmonston-Zagreb vaccine administered at 6 months of age induced antibody concentrations greater than or equal to 200 mIU/ml in 83% of infants by plaque reduction neutralization and 93% of infants by enzyme-linked immunosorbent assay with high rates of antibody persistence at 12 to 24 months of age. The World Health Organization recommends high titer Edmonston-Zagreb measles vaccines for routine use at 6 months of age in areas where measles is an important cause of mortality in young infants.     

Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses

BACKGROUND: Human herpesvirus type 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Primary infection causes an undifferentiated febrile illness, with approximately 30% of children exhibiting the classic clinical manifestations of exanthem subitum. Even with typical clinical presentation, exanthem subitum is frequently misdiagnosed as measles or rubella. Our aim was to describe the frequency and clinical manifestations of HHV-6 infection in children less than 4 years of age enrolled in a study designed to define the etiology of rash diseases. PATIENTS AND METHODS: The study was conducted between January 1998 and December 2006 at a general hospital and a large primary health care unit from Niterói, Rio de Janeiro, Brazil. Sera from 223 children, in whom measles, rubella, dengue fever, and parvovirus B19 infections were excluded, were studied for anti-HHV-6 antibodies using an indirect immunofluorescence test. Demographic and clinical data of those patients were described. RESULTS: Ninety-seven (43.5%) of the children had evidence of primary HHV-6 infection. The age of onset peaked at 6-11 months and 75% of the HHV-6 infection occurred in children between 6 and 17 months. Only 21% of the HHV-6 cases had a typical roseola-like illness and 73% and 46%, respectively, fulfilled the clinical criteria of measles and rubella suspected case. CONCLUSIONS: Our study confirms the importance of HHV-6 infection in young children and highlights the difficulties of diagnosing a rash illness on clinical grounds alone.     

Strong response of T cells in infants with dual infection by Epstein–Barr virus and cytomegalovirus

BACKGROUND: Although a reversed CD4/CD8 ratio and increased proportion of CD8+ HLA-DR+ T cells are well known as the characteristic immune response in infectious mononucleosis (IM), it has not been elucidated whether these immune responses are affected by patient age and pathogenetic viruses. METHODS: T cell subsets were analyzed by two-color flow cytometry using fluorescein isothiocyanate- and phycoerythrin-conjugated monoclonal antibodies in 115 infants and children aged from 4 months to 10 years with IM due to Epstein-Barr virus (EBV), cytomegalovirus (CMV) and dual infection with both viruses. RESULTS: A reversed CD4/CD8 ratio and increased proportions of CD4+/HLA-DR+ T cells, CD8+ T cells and CD8+/HLA-DR+ T cells became more prominent as the age of the patients became older. No differences were observed in proportions of T cell subsets between EBV- and CMV-infection among patients aged from 6 to 17 months. Although the responses of these T cells were weak in infants with single virus infection by EBV and CMV, markedly strong T cell responses comparable with those in older children were observed in infants with EBV/CMV dual infection. Clinical symptoms were more severe in patients with EBV/CMV dual infection than those with EBV or CMV alone. CONCLUSION: The manner of these T cell responses in the acute phase of IM was considered to be age dependent, although strong T cell responses and severe disease were observed in EBV/CMV dual infection irrespective of patient age.     

Measles and age of vaccination

Measles is responsible for high morbidity and mortality in children particularly in developing countries. Infants, found by analytical studies to constitute a high risk group, are usually not covered by current vaccination programmes. In Kuwait in the epidemic years during the period 1976-1982, the incidence of measles in infants under one year was found to be more than five times that in the population over one year of age, ranging between 758 and 992 per 100000 live births. During this period as many as one fifth of the total cases (13.3-21.7%) and about one-third of the total deaths (35%) occurred in infants. The mean fatality rate for infants under one year was 3.3 while for the population one year and above it was 1.4. As the immunity derived from the mother declines markedly a large majority of children over six months of age become susceptible to measles. There is a strong case for lowering the age of vaccination against measles to protect the infants, at least in the developing countries, and to control and eventually eradicate the disease.     

Acute lower respiratory infections: a major cause of death in children in Bangladesh

The importance of acute lower respiratory infections (ALRI) as a cause of death in children was estimated using systematically collected demographic data on the population of the Teknaf area of southern Bangladesh. Of 1349 children aged 1-59 months who died between 1 January 1982 and 31 December 1985, ALRI was diagnosed by verbal autopsy in 390 (29%) and was the leading cause of death. ALRI mortality rates were highest in the youngest age groups (136/1000 for those less than or equal to 5 months) and decreased in older children (16/1000 for those 3-4 years old). Half of all fatal ALRI cases occurred in children less than 6 months old. In older children, ALRI-associated deaths tended to occur during the months October to January, while deaths in infants tended to follow the seasonal birth pattern. Significant predisposing factors for fatal ALRI were malnutrition and measles, detected, respectively, in 18% and 8% of children who died from ALRI. This study emphasizes the importance of ALRI as a major cause of death in developing countries and suggests that interventions to reduce childhood mortality are needed and should be targeted to specific age groups at risk.     

Measles Vaccination V. The Booster Effect of Purified Hemagglutinin in Children Previously Immunized with this Product or Formalin-Killed Vaccine

Two groups of children immunized at the age of 6 months to two years with three monthly doses of either formalin-killed (FK) or Tween-ether (TE) measles vaccine were submitted to clinical and serological follow-up analysis up till 17 months after vaccination and then given a booster of TE vaccine of moderate potency. Among 8 cases of clearcut exposure to measles before the booster 6 responded with mild clinical symtoms; 3 without and 3 with a faint rash. An increase in HI serum titer was recorded in 3 out of the 6 cases. All of them had received FK vaccine. Between 11 and 17 months after vaccination no change in HI titers was demonstrable. After the booster the geometric mean HI titer increased 20 times in children primarily vaccinated with TE vaccine and 83 times in children given FK vaccine. In the pre-booster serum samples only 75 antibodies were detectable, where-as the post-booster serum samples in addition to 75 antibodies contained 1 to 3% 19S antibodies.     

Safety and immunogenicity of high-dose Edmonston-Zagreb measles vaccine in children with HIV-1 infection. A cohort study in Kigali, Rwanda.

OBJECTIVE--To compare the reactogenicity and immunogenicity of high-dose Edmonston-Zagreb (EZ) measles vaccine in children with and without human immunodeficiency virus, type 1 (HIV-1), infection. DESIGN--Prospective cohort study. SETTING--General pediatric clinic and home visits in Kigali, the capital of Rwanda. PARTICIPANTS--Infants born to HIV-1-seropositive and -seronegative mothers were vaccinated with a 10(5.0) 50% tissue culture infective dose of EZ measles vaccine at 6 months of age. Control visits were made 10 and 14 days later to monitor local and general reactions. Measles serum antibodies were measured by an enzyme-linked immunosorbent assay technique at birth and at 6 and 9 months of age. Three groups were compared: infected children (n = 43), uninfected children born to seropositive mothers (n = 135), and uninfected children born to seronegative mothers (n = 194). RESULTS--Three hundred twenty-three children (86.8%) were available for the reactogenicity study. No statistically significant difference between the three groups was found in the occurrence of minor adverse reactions. No severe adverse reaction was observed. One hundred ninety children (51.1%) were available for the immunogenicity study. The percentage of infants negative for measles antibody at 6 months was significantly higher (P = .021) in HIV-infected children (85%) and in uninfected children born to seropositive mothers (90%) than in uninfected children born to seronegative mothers (75%). The overall seroconversion rate at 9 months was 90% (95% confidence interval, 85.7% to 94.3%), without any statistically significant difference between the three groups. CONCLUSION--High-dose EZ vaccine administered at 6 months of age is safe and highly immunogenic in both HIV-infected and uninfected children.     

Augmented antibody response to live attenuated measles vaccine in children with Plasmodium falciparum parasitaemia

The impact of malarial infection on the humoral immunological response to measles virus antigen was studied in 184 children aged 8-19 months in Guinea-Bissau. Pre- and post-immunization measles serology was performed using dried blood on absorbent paper and the ELISA technique. Blood smears obtained at the time of vaccination and 2 and 4 weeks afterwards were examined for malaria parasites. Pre-vaccination antibodies to measles were found in 44 out of 184 children (24%). Plasmodium falciparum was identified in 62 of the 132 initially non-immune children who completed the study. The rate of seroconversion was 127 out of 132 (96%). Post-immunization measles antibody titres were significantly higher in the vaccinees with P. falciparum than in those without malaria parasites in the blood.     

Passive immunity of premature infants against measles during early infancy

The aim of this study was to evaluate the presence of transferred measles antibodies and seronegativity rates during early infancy in premature newborns whose mothers had infection-induced immunity. The premature group was composed of 22 and 35 newborns of gestational ages < 32 wk and > 32 wk, respectively, and the control group consisted of 28 term newborns. Enzyme-linked immunosorbent assay (ELISA) was used for the qualitative detection of IgG antibodies to measles virus. Mean cord blood relative values were significantly lower in both premature groups, < or = 32 wk (p < 0.0001) and > 32 wk (p < 0.001), when compared with term infants. No seronegative infant was found in the premature group at 2 mo of age. At 4 mo, the seronegativity rate was 27% for premature infants < or = 32 wk and 35% for those > 32 wk. At 6 mo, seronegativity increased to 86% and 74% for premature infants born at gestational ages < or = 32 wk and > 32 wk, respectively. Forty-six percent of the term infants became seronegative at that age. The differences between term infants and those in the two premature groups were statistically significant (p < 0.05 and p < 0.005). Premature infants, regardless of their prematurity degree, were thought to be more susceptible to measles infection than term ones at the age of 6 mo. Policies for their protection from measles infection are still to be investigated.     

Waning immunity to varicella in infants of human immunodeficiency virus-seropositive and -seronegative mothers

Immunity to varicella in HIV-exposed and -unexposed infants born to unvaccinated mothers, acquiring protective antibodies at birth declined to nonprotective (<1:8) levels by 5 months of age. Therefore, infants become susceptible to varicella before 12 months, which is the recommended time for varicella immunizations in the United States. Vaccination of susceptible HIV-seronegative women in the postpartum period may be important to consider.     

Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study

BACKGROUND: Previous studies have suggested that standard measles vaccine may reduce mortality by more than the number of deaths thought to be caused by measles infection in areas with high mortality. However, these observations have not been based on randomized trials. METHODS: During the recent war in Guinea-Bissau, most children fled from the city of Bissau and immunization services in the country broke down for several months. We were performing a trial in which children were randomized at 6 months of age to receive either measles vaccine or inactivated polio vaccine. Because of the war many children did not receive the dose of measles vaccine planned for 9 months of age. We were able to monitor mortality during the war and after. RESULTS: Included in the study were 433 children 6 to 11 months of age. Fifteen children died (3.6%) during the first 3 months of the war before vaccination programs were resumed, 4 of 214 measles-vaccinated children and 11 of 219 children who had received inactivated polio vaccine. The effect of measles vaccine was marked for girls [mortality rate ratio (MR), 0.00; 95% confidence limits, 0.0 to 0.37], whereas there was no difference for boys (MR = 1.02; 95% confidence limits, 0.25 to 3.88). In a combined analysis controlling for factors that differed between the two groups, the MR for measles-vaccinated children was 0.30 (95% confidence limits, 0.08 to 0.87). Prolonging the period of observation to the end of 1998 or including the prewar period did not modify the significant beneficial effect of measles vaccine for girls. Twenty-two of the children in the cohort were reported to have had measles, 8 cases occurring during the 3 months of the war. Exclusion of measles cases in the analysis did not change the results; children who had received measles vaccine had a MR of 0.28 (95% confidence limits, 0.06 to 0.89) during the first 3 months of the war. CONCLUSIONS: Consistent with previous observational studies, measles vaccination was associated with a reduction in mortality that cannot be explained by the prevention of measles infection. This nonspecific beneficial effect was particularly strong for girls. Further studies are needed to examine the extent of nonspecific effects in settings with high mortality.     

Placental transfer and decay of maternally acquired antimeasles antibodies in Nigerian children

BACKGROUND: In developing countries vaccination against measles virus (MV) is generally administered at 9 months of age, although it is well-documented that protection of most infants by passively acquired maternal MV antibodies is waning before immunization is given. The purpose of this study was to investigate the decay of maternally derived MV antibodies in Nigerian infants as well as to compare a German and Nigerian cohort of paired mothers and newborns regarding the placental transfer efficiency of MV-specific IgG and total IgG antibodies. METHODS: MV-specific IgG antibodies were measured with a commercially available MV-enzyme-linked immunosorbent assay, a recombinant hemagglutinin enzyme-linked immunosorbent assay as well as a neutralization assay. Total IgG values were determined with a standard immunoturbidimetric test. RESULTS: Anti-MV IgG titers were twice as high in German newborns as in Nigerian newborns. An increased concentration of immunoglobulins transferred via the placenta was found only in the German cohort. High concentrations of total maternal IgG reduced the concentration of MV-specific as well as total IgG that crossed the placenta. Furthermore only 17% of the 4-month-old Nigerian infants were still protected against measles. Antibodies had a biologic half-life of 33 days and a biochemical half-life of 48 days. CONCLUSIONS: Our findings demonstrate that the decay of passively acquired MV antibodies occurred even more rapidly than expected resulting in susceptibility to MV in most of the 4-month-old infants in Nigeria. Furthermore transfer of maternal anti-MV IgG and total IgG antibodies to the newborn was more efficient in the German cohort compared with the Nigerian group. These findings suggest the use of alternative vaccination strategies in developing countries to possibly reduce the window of susceptibility against measles.     

Seroepidemiology of measles in Delhi: implications for age of vaccination

Sero-epidemiological features of measles in Delhi were studied in 369 children. The study included 60 children who had history of measles in the past. Out of 369 random sera of children upto 8 years, 59·07% were found to be positive for measles antibody. The past history of measles was shown to be quite reliable as 91·6% of children with history of measles, showed high level of antibody for measles. However, 44·8% of 127 children with no positive history of measles were seropositive indicating previous sub-clinical infection. From the study it is concluded that the optimal age for vaccination in children is above 9 months.